Synthesis of 2-carboxamide cycloamino urea derivatives

ABSTRACT

Provided herein are processes useful for the preparation of 2-carboxamide cycloamino urea derivatives of formula (X), 
                         
and useful intermediates therefore, at internal temperatures such as less than about −5° C. to about −15° C. and using solvents such as tetrahydrofuran, bases such as amines, and the like.

FIELD OF INVENTION

The present invention is directed to processes for preparing2-carboxamide cycloamino urea derivatives, and useful intermediatestherefore.

BACKGROUND

The processes of the present invention are useful for the preparation ofalpha-selective phosphatidylinositol (PI) 3-kinase inhibitor compoundsaccording to formula (X), and intermediates therefore.Phosphatidylinositol 3-kinases (PI3Ks) comprise a family of lipidkinases that catalyze the transfer of phosphate to the D-3′ position ofinositol lipids to produce phosphoinositol-3-phosphate (PIP),phosphoinositol-3,4-diphosphate (PIP2) andphosphoinositol-3,4,5-triphosphate (PIP3), which, in turn, act as secondmessengers in signaling cascades by docking proteins containingpleckstrin-homology, FYVE, Phox and other phospholipid-binding domainsinto a variety of signaling complexes often at the plasma membrane.

PCT Publication No. WO 2010/029082 discloses PI3K inhibitors. Thecompounds disclosed therein include (S)-pyrrolidine-1,2-dicarboxylicacid 2-amide1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide)(i.e., the compound of formula (10)). The present invention is directedto improved processes for preparing compounds of the formula (X),specifically the compound of formula (10), as well as usefulintermediates such as compounds of the formula (I), specifically thecompound of formula (1):

SUMMARY OF THE INVENTION

Provided herein are processes for the preparation of compounds offormula (X). Also provided herein are intermediate compounds, as well asmethods of making those intermediates, that are useful for thepreparation of compounds of formula (X). The compounds of formulas(I)-(X) and the compounds of formulas (1) to (8) and (10) refer to thecompounds as defined in the description herein.

In one aspect, provided herein is a process for making a compound offormula (V)

comprising contacting a compound of formula (I) with a solvent and abase and contacting the resulting mixture with a compound of formula(II), such that a compound of formula (III) is produced (STEP A). Thecompound of formula (III) is then contacted with thiourea, in a reactionmixture comprising a solvent and an oxidizing agent, such that acompound of formula (V) is produced (STEP B).

In another aspect, provided herein is a process for making a compound offormula (X)

comprising contacting a compound of formula (V) with a compound offormula (VII), in a reaction mixture comprising a solvent and a base,such that a compound of formula (VIII) is produced (STEP C). Thecompound of formula (VIII) is then contacted with the compound offormula (IX) in a reaction mixture comprising a solvent, such that acompound of formula (X) is produced (STEP D).

In still another aspect, provided herein is a process for making acompound of formula (X), comprising contacting a compound of formula (I)with a solvent and a base, and contacting the resulting mixture with acompound of formula (II), such that a compound of formula (III) isproduced (STEP A); contacting a compound of formula (III) with thiourea,in a reaction mixture comprising a solvent and an oxidizing agent, suchthat a compound of formula (V) is produced (STEP B); contacting acompound of formula (V) with a compound of formula (VII), in a reactionmixture comprising a solvent and a base, such that a compound of formula(VIII) is produced (STEP C); and contacting a compound of formula (VIII)with the compound of formula (IX) in a reaction mixture comprising asolvent, such that a compound of formula (X) is produced (STEP D).

In accordance with the present invention, the solvent of Step Acomprises one or more solvents selected from aromatic solvents,aliphatic solvents, halogenated solvents, polar aprotic solvents andethereal solvents.

In accordance with the present invention, the solvent of Steps B, C andD independently comprises one or more solvents selected from aromaticsolvents, aliphatic solvents, halogenated solvents, ethereal solvents,polar aprotic solvents, water and alcohol solvents.

In yet another aspect, provided herein is a process for making thecompound of formula (10), comprising contacting the compound of formula(1) with a solvent and a base, and contacting the resulting mixture witha compound of formula (2), such that the compound of formula (3) isproduced (STEP A). The compound of formula (3) is then contacted withthiourea, in a reaction mixture comprising a solvent and an oxidizingagent, such that the compound of formula (5) is produced (STEP B). Thecompound of formula (5) is next contacted with the compound of formula(7), in a reaction mixture comprising a solvent and a base, such thatthe compound of formula (8) is produced (STEP C). Finally, the compoundof formula (8) is contacted with the compound of formula (IX), in areaction mixture comprising a solvent, such that the compound of formula(10) is produced (STEP D).

In one embodiment of the synthesis of the compound of formula (10), thesolvent of Step A comprises tetrahydrofuran, the base of Step A islithium diisopropylamide, the solvent of Step B comprises toluene andethanol, the oxidizing agent of Step B is N-bromosuccinimide, thesolvent of Step C comprises tetrahydrofuran, the base of Step C ispyridine and the solvent of Step D comprises tetrahydrofuran and water.

In another aspect, provided herein is a compound according to formula(1).

DETAILED DESCRIPTION

Provided herein are processes and intermediate compounds useful for thepreparation of PI3K inhibitors. These processes are advantageous overpreviously-known processes (see, e.g., PCT Publication No. WO2010/029082) in several ways. For example, the instant processes do notemploy transition metal-catalyzed reactions, and therefore do notrequire steps to remove transition metal byproducts, residues andimpurities. Additionally, the instant processes do not require reactionsto be performed at very low temperatures (e.g., −78° C.).

In one aspect of the present invention, provided herein is a process formaking a compound of formula (V), comprising the following steps:

Step A: contacting a compound of formula (I) with a solvent and a base,and contacting the resulting mixture with a compound of formula (II),such that a compound of formula (III) is produced:

and

Step B: contacting a compound of formula (III) with thiourea, in areaction mixture comprising a solvent and an oxidizing agent [X+], suchthat a compound of formula (V) is produced:

wherein R₁ is a cyclic or acyclic, branched or linear C₁-C₇ alkyl, whichmay be optionally substituted one or more times with deuterium, halogen,or C₃-C₅ cycloalkyl; and

wherein R₂ is selected from (1) hydrogen, (2) fluoro, chloro, (3)optionally substituted methyl, wherein said substituents areindependently selected from one or more, preferably one to three of thefollowing moieties: deuterium, fluoro, chloro, dimethylamino; and

wherein X is selected from the group consisting of halide, carboxylateand sulfonate.

In another aspect, provided herein is a process for making a compound offormula (X), comprising the following steps:

Step C: contacting a compound of formula (V) with a compound of formula(VII), in a reaction mixture comprising a solvent and a base, such thata compound of formula (VIII) is produced:

and

Step D: contacting a compound of formula (VIII) with the compound offormula (IX), in a reaction mixture comprising a solvent, such that acompound of formula (X) is produced:

wherein R₁ is a cyclic or acyclic, branched or linear C₁-C₇ alkyl, whichmay be optionally substituted one or more times with deuterium, halogen,or C₃-C₅ cycloalkyl; and

wherein R₂ is selected from (1) hydrogen, (2) fluoro, chloro, (3)optionally substituted methyl, wherein said substituents areindependently selected from one or more, preferably one to three of thefollowing moieties: deuterium, fluoro, chloro, dimethylamino; and

wherein X is selected from the group consisting of halide, carboxylateand sulfonate; and

wherein R₃ and R₄ are independently selected from the group consistingof halogen, heteroaryl, alkoxy and aryloxy; and

wherein the heteroaryl, alkoxy and aryloxy moieties of R₃ and R₄ areoptionally, independently substituted one or more times with alkyl,alkoxy, halogen and nitro.

In still another aspect, provided herein is a process for making acompound of formula (X), comprising the following steps: Step A:contacting a compound of formula (I) with a solvent and a base, andcontacting the resulting mixture with a compound of formula (II), suchthat a compound of formula (III) is produced; Step B: contacting acompound of formula (III) with thiourea, in a reaction mixturecomprising a solvent and an oxidizing agent, such that a compound offormula (V) is produced; Step C: contacting a compound of formula (V)with a compound of formula (VII), in a reaction mixture comprising asolvent and a base, such that a compound of formula (VIII) is produced;and Step D: contacting a compound of formula (VIII) with the compound offormula (IX), in a reaction mixture comprising a solvent, such that acompound of formula (X) is produced; wherein R₁, R₂, R₃, R₄ and X are asdefined above.

In accordance with the present invention, the solvent of Step Acomprises one or more solvents selected from aromatic solvents,aliphatic solvents, halogenated solvents, polar aprotic solvents andethereal solvents. Numerous examples of these solvents are known tothose with skill in the art. Non-limiting examples of aromatic solventsinclude benzene, toluene, xylenes, nitrobenzene, anisole, ethylbenzene,and pyridine. Non-limiting examples of aliphatic solvents includepetroleum ether, ligroin, n-hexane, cyclohexane and heptane.Non-limiting examples of halogenated solvents include chloroform,chlorobenzene and perfluorohexane. Non-limiting examples of polaraprotic solvents include dimethylsulfoxide, dimethylformamide andN-methyl pyrrolidone. Non-limiting examples of ethereal solvents includediethyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and dimethoxyethane. In certain embodiments, the solventof Step A is an aprotic, organic solvent. In preferred embodiments, thesolvent of Step A comprises tetrahydrofuran.

In accordance with the present invention, the solvent of Steps B, C andD independently comprises one or more solvents selected from aromaticsolvents, aliphatic solvents, halogenated solvents, ethereal solvents,polar aprotic solvents, water and alcohol solvents. Non-limitingexamples of alcohol solvents include ethanol, tertiary-butanol andethylene glycol. Other alcohol solvents are known to those skilled inthe art. In certain embodiments, the solvent of Step B comprises anaromatic solvent and an alcohol solvent. In a preferred embodiment, thesolvent of Step B comprises toluene and ethanol. In certain embodiments,the solvent of Step C comprises an ethereal solvent. In a preferredembodiment, the solvent of Step C comprises tetrahydrofuran. In certainembodiments, the solvent of Step D comprises and ethereal solvent andwater. In a preferred embodiment, the solvent of Step D comprisestetrahydrofuran and water.

In accordance with the present invention, the base of Step A is a strongbase. Strong bases include the conjugate bases of hydrocarbons, ammonia,amines and dihydrogen. Non-limiting examples of strong bases includen-butyllithium, n-hexyllithium, sodium hydride and lithiumdiisopropylamide. Other strong bases are known to those skilled in theart. In certain embodiments, the base of Step A is lithiumdiisopropylamide. Methods of preparing lithium diisopropylamide areknown to those of skill in the art (see, e.g., Smith, A. P.; Lamba, J.J. S.; Fraser, C. L., Org. Syn. Col. Vol. 10: 107, (2004)). In oneembodiment, the lithium diisopropylamide is prepared by thedeprotonation of isopropylamine with an alkyllithium base such asn-butyllithium, n-hexyllithium or n-octyllithium. Safety and economicconsiderations may influence the selection of reagents used for thepreparation of lithium diisopropylamide (see, e.g., Chapter 3: ReagentSelection, in “Practical Process Research and Development”, AcademicPress, 2000). In one embodiment, the lithium diisopropylamide isprepared by the deprotonation of diisopropylamine with n-hexyllithium.One of skill in the art would understand that solutions of lithiumdiisopropylamide in certain solvents, such as THF, should be maintainedat temperatures equal to or below 0° C.

In one embodiment of the above processes, the base of Step C is anamine. Non-limiting examples of amine bases include tertiary-butylamine,piperidine, triethylamine, 1,8-Diazabicyclo[5.4.0]undec-7-ene andpyridine. Other amine bases are known to those skilled in the art. Incertain embodiments, the base of Step C is pyridine.

In accordance with the present invention, the oxidizing agent of Step Bis an electrophilic halogen reagent. Numerous electrophilic halogenreagents are known to the skilled practitioner, including dibromine,diiodine, dichlorine, sulfuryl chloride, N-bromosuccinimide,N-iodosuccinimide, N-chlorosuccinimide and1,3-dibromo-5,5-dimethylhydantoin. In certain embodiments, the oxidizingagent of Step B is N-bromosuccinimide.

In one embodiment of the present invention, the oxidizing agent of StepB is N-bromosuccinimide, and the subsequent mixture is diluted with ananti-solvent agent. In a preferred embodiment, the anti-solvent isisopropyl acetate.

In accordance with the present invention, X is selected from the groupconsisting of halide, carboxylate, and sulfonate. In certainembodiments, X is a halide. In a preferred embodiment, X is bromine.

In a preferred embodiment of the above processes, the solvent of Step Acomprises tetrahydrofuran, the base of Step A is lithiumdiisopropylamide, the solvent of Step B comprises toluene and ethanol,the oxidizing agent of Step B is N-bromosuccinimide, the solvent of StepC comprises tetrahydrofuran, the base of Step C is pyridine and thesolvent of Step D comprises tetrahydrofuran and water.

In various embodiments of the above processes, R₁ is a cyclic oracyclic, branched or linear C₁-C₇ alkyl, all of which may be optionallysubstituted one or more times with deuterium, halogen, or C₃-C₅cycloalkyl. In other embodiments, R₁ is a branched or linear C₁-C₇ alkylthat is optionally substituted one or more times with halogen. In apreferred embodiment, R₁ is

In various embodiments of the above processes, R₂ represents (1)hydrogen, (2) fluoro, chloro, (3) optionally substituted methyl, whereinsaid substituents are independently selected from one or more,preferably one to three of the following moieties: deuterium, fluoro,chloro, dimethylamino. In certain embodiments, R₂ is selected fromhydrogen, cyclic or acyclic, branched or linear C₁-C₇ alkyl, and halogenwherein the alkyl is optionally substituted one or more times withdeuterium, fluorine, chlorine and dimethylamino. In other embodiments,R₂ is a branched or linear C₁-C₇ alkyl. In a preferred embodiment, R₂ ismethyl.

In various embodiments, R₃ and R₄ are independently selected from thegroup consisting of halogen, heteroaryl, alkoxy and aryloxy; wherein theheteroaryl, alkoxy and aryloxy moieties of R₃ and R₄ are optionally,independently substituted one or more times with alkyl, alkoxy, halogenand nitro. In certain embodiments, R₃ is aryloxy and R₄ are bothheteroaryl. In other embodiments, R₃ is aryloxy and R₄ is halogen. In apreferred embodiment, R₃ is phenoxy and R₄ is chlorine.

In a preferred embodiment of the above processes, R₁ is

R₂ is methyl, R₃ is phenoxy, R₄ is chlorine and X is bromine.

In one embodiment of the present invention, the compound of formula (I)is first contacted with the compound of formula (II) in a reactionmixture comprising a base and solvent, and second optionally contactedwith a reaction mixture comprising an aqueous acid or base resulting inthe pH of the aqueous phase to be within the range 2<pH<4, preferably pH3. Preferably, the base is lithium diisopropylamide and the firstsolvent is THF, wherein the reaction mixture is maintained such that theinternal temperature remains less than −5° C., preferably at −15° C.Preferably, the pH of the aqueous phase is adjusted to pH 3 with areaction mixture comprising sulfuric acid, water and toluene.

In one embodiment of the present invention, the compound of formula(VIII) is contacted with the compound of formula (IX) in a reactionmixture comprising a first solvent, such that the compound of formula(X) is formed. An aromatic solvent is then added to the mixture,followed by removal of the first solvent by distillation, resulting inthe precipitation of the compound of formula (X). Preferably, thearomatic solvent is toluene.

In another aspect of the present invention, provided herein is a processfor making the compound of formula (10), comprising the following steps:

Step A: contacting the compound of formula (1) with a solvent and abase, and contacting the resulting mixture with the compound of formula(2), such that the compound of formula (3) is produced:

Step B: contacting the compound of formula (3) with thiourea, in areaction mixture comprising a solvent and an oxidizing agent [Br+], suchthat the compound of formula (5) is produced:

Step C: contacting the compound of formula (5) with the compound offormula (7), in a reaction mixture comprising a solvent and a base, suchthat the compound of formula (8) is produced:

and

Step D: contacting the compound of formula (8) with the compound offormula (IX), in a reaction mixture comprising a solvent, such that thecompound of formula (10) is produced:

In accordance with this aspect of the present invention, the solvent ofStep A comprises one or more solvents selected from aromatic solvents,aliphatic solvents, halogenated solvents, polar aprotic solvents andethereal solvents. Numerous examples of these solvents are known tothose with skill in the art. Non-limiting examples of aromatic solventsinclude benzene, toluene, xylenes, nitrobenzene, anisole, ethylbenzene,and pyridine. Non-limiting examples of aliphatic solvents includepetroleum ether, ligroin, n-hexane, cyclohexane and heptane.Non-limiting examples of halogenated solvents include chloroform,chlorobenzene and perfluorohexane. Non-limiting examples of polaraprotic solvents include dimethylsulfoxide, dimethylformamide andN-methyl pyrrolidone. Non-limiting examples of ethereal solvents includediethyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and dimethoxyethane. In certain embodiments, the solventof Step A is an aprotic, organic solvent. In preferred embodiments, thesolvent of Step A comprises tetrahydrofuran.

In accordance with this aspect of the present invention, the solvent ofSteps B, C and D independently comprises one or more solvents selectedfrom aromatic solvents, aliphatic solvents, halogenated solvents,ethereal solvents, polar aprotic solvents, water and alcohol solvents.Non-limiting examples of alcohol solvents include ethanol,tertiary-butanol and ethylene glycol. Other alcohol solvents are knownto those skilled in the art. In certain embodiments, the solvent of StepB comprises an aromatic solvent and an alcohol solvent. In a preferredembodiment, the solvent of Step B comprises toluene and ethanol. Incertain embodiments, the solvent of Step C comprises an etherealsolvent. In a preferred embodiment, the solvent of Step C comprisestetrahydrofuran. In certain embodiments, the solvent of Step D comprisesand ethereal solvent and water. In a preferred embodiment, the solventof Step D comprises tetrahydrofuran and water.

In accordance with this aspect of the present invention, the base ofStep A is a strong base. Strong bases include the conjugate bases ofhydrocarbons, ammonia, amines and dihydrogen. Non-limiting examples ofstrong bases include n-butyllithium, n-hexyllithium, sodium hydride andlithium diisopropylamide. Other strong bases are known to those skilledin the art. In certain embodiments, the base of Step A is lithiumdiisopropylamide. Methods of preparing lithium diisopropylamide areknown to those of skill in the art (see, e.g., Smith, A. P.; Lamba, J.J. S.; Fraser, C. L., Org. Syn. Col. Vol. 10: 107, (2004)). In oneembodiment, the lithium diisopropylamide is prepared by thedeprotonation of isopropylamine with an alkyllithium base such asn-butyllithium, n-hexyllithium or n-octyllithium. Safety and economicconsiderations may influence the selection of reagents used for thepreparation of lithium diisopropylamide (see, e.g., Chapter 3: ReagentSelection, in “Practical Process Research and Development”, AcademicPress, 2000). In one embodiment, the lithium diisopropylamide isprepared by the deprotonation of diisopropylamine with n-hexyllithium.One of skill in the art would understand that solutions of lithiumdiisopropylamide in certain solvents, such as THF, should be maintainedat temperatures equal to or below 0° C.

In a further embodiment of the above processes of the present invention,the base of Step C is an amine. Non-limiting examples of amine basesinclude tertiary-butylamine, piperidine, triethylamine,1,8-Diazabicyclo[5.4.0]undec-7-ene and pyridine. Other amine bases areknown to those skilled in the art. In certain embodiments, the base ofStep C is pyridine.

In one embodiment of the above processes of the present invention, theoxidizing agent of Step B is an electrophilic halogen reagent. Numerouselectrophilic halogen reagents are known to the skilled practitioner,including dibromine, diiodine, dichlorine, sulfuryl chloride,N-bromosuccinimide, N-iodosuccinimide, N-chlorosuccinimide and1,3-dibromo-5,5-dimethylhydantoin. In certain embodiments, the oxidizingagent of Step B is N-bromosuccinimide.

In one embodiment of the present invention, the oxidizing agent of StepB is N-bromosuccinimide, and the subsequent mixture is diluted with ananti-solvent agent. In a preferred embodiment, the anti-solvent isisopropyl acetate.

In a preferred embodiment of the synthesis of the compound of formula(10), the solvent of Step A comprises tetrahydrofuran, the base of StepA is lithium diisopropylamide, the solvent of Step B comprises tolueneand ethanol, the oxidizing agent of Step B is N-bromosuccinimide, thesolvent of Step C comprises tetrahydrofuran, the base of Step C ispyridine and the solvent of Step D comprises tetrahydrofuran and water.

In one embodiment of the present invention, the compound of formula (1)is first contacted with the compound of formula (2) in a reactionmixture comprising a base and solvent, and second optionally contactedwith a reaction mixture comprising an aqueous acid or base resulting inthe pH of the aqueous phase to be within the range 2<pH<4, preferably pH3. Preferably, the base is lithium diisopropylamide and the firstsolvent is THF, wherein the reaction mixture is maintained such that theinternal temperature remains less than −5° C., preferably at −15° C.Preferably, the pH of the aqueous phase is adjusted to pH 3 with areaction mixture comprising sulfuric acid, water and toluene.

In one embodiment of the present invention, the compound of formula (5)is contacted with the compound of formula (7) in a reaction mixturecomprising the solvent THF and the base pyridine, and then the basepyridine is removed by addition of saturated saline or aqueous salt(preferably sodium chloride) solution. In one embodiment of the presentinvention, the compound of formula (8) is contacted with the compound offormula (IX) in a reaction mixture comprising a first solvent, such thatthe compound of formula (10) is formed. An aromatic solvent is thenadded to the mixture, followed by removal of the first solvent bydistillation, resulting in the precipitation of the compound of formula(10). Preferably, the aromatic solvent is toluene.

In another aspect of the invention, provided herein is a compoundaccording to formula (1):

The compound of formula (1) is particularly useful as a startingmaterial, or an intermediate, in the preparation of the compound offormula (10), as well as chemical analogues of the compound of formula(10). The compound of formula (1) can be synthesized in accordance withthe preparation methods set forth in Scheme 4 or Scheme 5 herein.

The skilled practitioner will recognize several parameters of theforegoing processes that may be varied advantageously in order to obtaina desirable outcome. These parameters include, for example, the methodsand means of purification of reaction components and solvents; the orderof addition of said reaction components and solvents to the reactionmixture; the duration of reaction of said reaction components andsolvents; and the temperature and rate of stirring, mixing or agitationof the reaction components and solvents during said reaction.

DEFINITIONS

As used herein, the term “lower” or “C₁-C₇” denotes a radical having upto and including a maximum of 7, especially up to and including amaximum of 4 carbon atoms, the radicals in question being either linearor branched with single or multiple branching.

As used herein, the term “alkyl” refers to a straight-chain orbranched-chain alkyl group, preferably represents a straight-chain orbranched-chain C₁₋₁₂alkyl, particularly preferably represents astraight-chain or branched-chain C₁₋₇alkyl; for example, methyl, ethyl,n- or iso-propyl, n-, iso-, sec- or tert-butyl, n-pentyl, n-hexyl,n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, withparticular preference given to methyl, ethyl, n-propyl, iso-propyl andn-butyl and iso-butyl. Alkyl may be unsubstituted or substituted.Exemplary substituents include, but are not limited to deuterium,hydroxy, alkoxy, halo and amino. An example of a substituted alkyl istrifluoromethyl. Cycloalkyl may also be a substituent to alkyl. Anexample of such a case is the moiety (alkyl)-cyclopropyl oralkandiyl-cycloproyl, e.g. —CH₂-cyclopropyl. C₁-C₇-alkyl is preferablyalkyl with from and including 1 up to and including 7, preferably fromand including 1 to and including 4, and is linear or branched;preferably, lower alkyl is butyl, such as n-butyl, sec-butyl, isobutyl,tert-butyl, propyl, such as n-propyl or isopropyl, ethyl or preferablymethyl.

Each alkyl part of other groups like “alkoxy”, “alkoxyalkyl”,“alkoxycarbonyl”, “alkoxy-carbonylalkyl”, “alkylsulfonyl”,“alkylsulfoxyl”, “alkylamino”, “haloalkyl” shall have the same meaningas described in the above-mentioned definition of “alkyl”

As used herein, the term “alkandiyl” refers to a straight-chain orbranched-chain alkandiyl group bound by two different Carbon atoms tothe moiety, it preferably represents a straight-chain or branched-chainC₁₋₁₂ alkandiyl, particularly preferably represents a straight-chain orbranched-chain C₁₋₆ alkandiyl; for example, methandiyl (—CH₂—),1,2-ethanediyl (—CH₂—CH₂—), 1,1-ethanediyl ((—CH(CH₃)—), 1,1-, 1,2-,1,3-propanediyl and 1,1-, 1,2-, 1,3-, 1,4-butanediyl, with particularpreference given to methandiyl, 1,1-ethanediyl, 1,2-ethanediyl,1,3-propanediyl, 1,4-butanediyl.

As used herein, the term “cycloalkyl” refers to a saturated or partiallysaturated, monocyclic, fused polycyclic, or Spiro polycyclic, carbocyclehaving from 3 to 12 ring atoms per carbocycle. Illustrative examples ofcycloalkyl groups include the following moieties: cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl may be unsubstitutedor substituted; exemplary substituents are provided in the definitionfor alkyl and also include alkyl itself (e.g. methyl). A moiety like—(CH₃)cyclopropyl is considered substituted cycloalkyl.

As used herein, the term “aryl” refers to an aromatic homocyclic ringsystem (i.e. only Carbon as ring forming atoms) with 6 or more carbonatoms; aryl is preferably an aromatic moiety with 6 to 14 ring carbonatoms, more preferably with 6 to 10 ring carbon atoms, such as phenyl ornaphthyl, preferably phenyl. Aryl may be unsubstituted or substituted byone or more, preferably up to three, more preferably up to twosubstituents independently selected from the group consisting ofunsubstituted or substituted heterocyclyl as described below, especiallypyrrolidinyl, such as pyrrolidino, oxopyrrolidinyl, such asoxopyrrolidino, C₁-C₇-alkyl-pyrrolidinyl,2,5-di-(C₁-C₇alkyl)pyrrolidinyl, such as2,5-di-(C₁-C₇alkyl)-pyrrolidino, tetrahydrofuranyl, thiophenyl,C₁-C₇-alkylpyrazolidinyl, pyridinyl, C₁-C₇-alkylpiperidinyl, piperidino,piperidino substituted by amino or N-mono- or N,N-di-[lower alkyl,phenyl, C₁-C₇-alkanoyl and/or phenyl-lower alkyl)-amino, unsubstitutedor N-lower alkyl substituted piperidinyl bound via a ring carbon atom,piperazino, lower alkylpiperazino, morpholino, thiomorpholino,S-oxo-thiomorpholino or S,S-dioxothiomorpholino; C₁-C₇-alkyl,amino-C₁-C₇-alkyl, N—C₁-C₇-alkanoylamino-C₁-C₇-alkyl,N—C₁-C₇-alkanesulfonyl-amino-C₁-C₇-alkyl, carbamoyl-C₁-C₇-alkyl,[N-mono- or N,N-di-(C₁-C₇-alkyl)-carbamoyl]-C₁-C₇-alkyl,C₁-C₇-alkanesulfinyl-C₁-C₇-alkyl, C₁-C₇-alkanesulfonyl-C₁-C₇-alkyl,phenyl, naphthyl, mono- to tri-[C₁-C₇-alkyl, halo and/or cyano]-phenylor mono- to tri-[C₁-C₇-alkyl, halo and/or cyano]-naphthyl;C₃-C₈-cycloalkyl, mono- to tri-[C₁-C₇-alkyl and/orhydroxy]-C₃-C₈-cycloalkyl; halo, hydroxy, lower alkoxy,lower-alkoxy-lower alkoxy, (lower-alkoxy)-lower alkoxy-lower alkoxy,halo-C₁-C₇-alkoxy, phenoxy, naphthyloxy, phenyl- or naphthyl-loweralkoxy; amino-C₁-C₇-alkoxy, lower-alkanoyloxy, benzoyloxy, naphthoyloxy,formyl (CHO), amino, N-mono- or N,N-di-(C₁-C₇-alkyl)-amino,C₁-C₇-alkanoylamino, C₁-C₇-alkanesulfonylamino, carboxy, lower alkoxycarbonyl, e.g.; phenyl- or naphthyl-lower alkoxycarbonyl, such asbenzyloxycarbonyl; C₁-C₇-alkanoyl, such as acetyl, benzoyl, naphthoyl,carbamoyl, N-mono- or N,N-disubstituted carbamoyl, such as N-mono- orN,N-di-substituted carbamoyl wherein the substitutents are selected fromlower alkyl, (lower-alkoxy)-lower alkyl and hydroxy-lower alkyl;amidino, guanidino, ureido, mercapto, lower alkylthio, phenyl- ornaphthylthio, phenyl- or naphthyl-lower alkylthio, loweralkyl-phenylthio, lower alkyl-naphthylthio, halo-lower alkylmercapto,sulfo (—SO₃H), lower alkanesulfonyl, phenyl- or naphthyl-sulfonyl,phenyl- or naphthyl-lower alkylsulfonyl, alkylphenylsulfonyl, halo-loweralkylsulfonyl, such as trifluorome-thanesulfonyl; sulfonamido,benzosulfonamido, azido, azido-C₁-C₇-alkyl, especially azidomethyl,C₁-C₇-alkanesulfonyl, sulfamoyl, N-mono- orN,N-di-(C₁-C₇-alkyl)-sulfamoyl, morpholinosulfonyl,thiomorpholinosulfonyl, cyano and nitro; where each phenyl or naphthyl(also in phenoxy or naphthoxy) mentioned above as substituent or part ofa substituent of substituted alkyl (or also of substituted aryl,heterocyclyl etc. mentioned herein) is itself unsubstituted orsubstituted by one or more, e.g. up to three, preferably 1 or 2,substituents independently selected from halo, halo-lower alkyl, such astrifluoromethyl, hydroxy, lower alkoxy, azido, amino, N-mono- orN,N-di-(lower alkyl and/or C₁-C₇-alkanoyl)-amino, nitro, carboxy,lower-alkoxycarbonyl, carbamoyl, cyano and/or sulfamoyl.

The term “aryloxy” refers to a moiety comprising an oxygen atom that issubstituted with an aryl group, as defined above.

The term “heteroaryl,” as used herein, represents a stable monocyclic orbicyclic ring of up to 7 atoms in each ring, wherein at least one ringis aromatic and contains from 1 to 4 heteroatoms selected from the groupconsisting of O, N and S. Heteroaryl groups within the scope of thisdefinition include but are not limited to: acridinyl, carbazolyl,cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl,thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl,oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, tetrahydroquinoline. As with the definition ofheterocycle below, “heteroaryl” is also understood to include theN-oxide derivative of any nitrogen-containing heteroaryl. In cases wherethe heteroaryl substituent is bicyclic and one ring is non-aromatic orcontains no heteroatoms, it is understood that attachment is via thearomatic ring or via the heteroatom containing ring, respectively.

As used herein, the term “heterocycle” or “heterocyclyl” refers to aheterocyclic radical that is unsaturated (=carrying the highest possiblenumber of conjugated double bonds in the ring(s)), saturated orpartially saturated and is preferably a monocyclic or in a broaderaspect of the invention bicyclic, tricyclic or spirocyclic ring; and has3 to 24, more preferably 4 to 16, most preferably 5 to 10 and mostpreferably 5 or 6 ring atoms; wherein one or more, preferably one tofour, especially one or two ring atoms are a heteroatom (the remainingring atoms therefore being carbon). The bonding ring (i.e. the ringconnecting to the molecule) preferably has 4 to 12, especially 5 to 7ring atoms. The term heterocyclyl also includes heteroaryl. Theheterocyclic radical (heterocyclyl) may be unsubstituted or substitutedby one or more, especially 1 to 3, substituents independently selectedfrom the group consisting of the substituents defined above forsubstituted alkyl and/or from one or more of the following substituents:oxo (═O), thiocarbonyl (═S), imino (═NH), imino-lower alkyl. Further,heterocyclyl is especially a heterocyclyl radical selected from thegroup consisting of oxiranyl, azirinyl, aziridinyl, 1,2-oxathiolanyl,thienyl (=thiophenyl), furanyl, tetrahydrofuryl, pyranyl, thiopyranyl,thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl,pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl,benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl,isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl,pyrimidinyl, piperidinyl, piperazinyl, pyridazinyl, morpholinyl,thiomorpholinyl, (S-oxo or S,S-dioxo)-thiomorpholinyl, indolizinyl,azepanyl, diazepanyl, especially 1,4-diazepanyl, isoindolyl, 3H-indolyl,indolyl, benzimidazolyl, cumaryl, indazolyl, triazolyl, tetrazolyl,purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, tetrahydroquinolyl,tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl,benzofuranyl, dibenzofuranyl, benzothiophenyl, dibenzothiophenyl,phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, quinazolinyl,cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl,acridinyl, perimidinyl, phenanthrolinyl, furazanyl, phenazinyl,phenothiazinyl, phenoxazinyl, chromenyl, isochromanyl, chromanyl,benzo[1,3]dioxol-5-yl and 2,3-dihydro-benzo[1,4]dioxin-6-yl, each ofthese radicals being unsubstituted or substituted by one or more,preferably up to three, substituents selected from those mentioned abovefor substituted aryl and/or from one or more of the followingsubstituents: oxo (═O), thiocarbonyl (═S), imino (═NH), imino-loweralkyl.

The term “heteroatoms” are atoms other than Carbon and Hydrogen,preferably nitrogen (N), oxygen (O) or sulfur (S), in particularnitrogen.

Moreover, the alkyl, alkoxy, aryl, aryloxy and heteroaryl groupsdescribed above can be “unsubstituted” or “substituted.” The term“substituted” is intended to describe moieties having substituentsreplacing a hydrogen on one or more atoms, e.g. C, O or N, of amolecule. Such substituents can independently include, for example, oneor more of the following: straight or branched alkyl (preferably C₁-C₅),cycloalkyl (preferably C₃-C₈), alkoxy (preferably C₁-C₆), thioalkyl(preferably C₁-C₆), alkenyl (preferably C₂-C₆), alkynyl (preferablyC₂-C₆), heterocyclic, carbocyclic, aryl (e.g., phenyl), aryloxy (e.g.,phenoxy), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenyloxyalkyl),arylacetamidoyl, alkylaryl, heteroaralkyl, alkylcarbonyl andarylcarbonyl or other such acyl group, heteroarylcarbonyl, or heteroarylgroup, (CR′R″)₀₋₃NR′R″ (e.g., —NH₂), (CR′R″)₀₋₃CN (e.g., —CN), —NO₂,halogen (e.g., —F, —Cl, —Br, or —I), (CR′R″)₀₋₃C(halogen)₃ (e.g., —CF₃),(CR′R″)₀₋₃CH(halogen)₂, (CR′R″)₀₋₃CH₂(halogen), (CR′R″)₀₋₃CONR′R″,(CR′R″)₀₋₃(CNH)NR′R″, (CR′R″)₀₋₃S(O)₁₋₂NR′R″, (CR′R″)₀₋₃CHO,(CR′R″)₀₋₃O(CR′R″)₀₋₃H, (CR′R″)₀₋₃S(O)₀₋₃R′ (e.g., —SO₃H, —OSO₃H),(CR′R″)₀₋₃O(CR′R″)₀₋₃H (e.g., —CH₂OCH₃ and —OCH₃),(CR′R″)₀₋₃S(CR′R″)₀₋₃H (e.g., —SH and —SCH₃), (CR′R″)₀₋₃OH (e.g., —OH),(CR′R″)₀₋₃COR′, (CR′R″)₀₋₃(substituted or unsubstituted phenyl),(CR′R″)₀₋₃(C₃-C₈ cycloalkyl), (CR′R″)₀₋₃CO₂R′ (e.g., —CO₂H), or(CR′R″)₀₋₃OR′ group, or the side chain of any naturally occurring aminoacid; wherein R′ and R″ are each independently hydrogen, a C₁-C₅ alkyl,C₂-C₅ alkenyl, C₂-C₅ alkynyl, or aryl group.

As used herein, the term “halogen” or “halo” refers to fluorine,bromine, chlorine or iodine, in particular fluorine, chlorine.Halogen-substituted groups and moieties, such as alkyl substituted byhalogen (haloalkyl) can be mono-, poly- or per-halogenated.

The term “amine” or “amino” should be understood as being broadlyapplied to both a molecule, or a moiety or functional group, asgenerally understood in the art, and may be primary, secondary, ortertiary. The term “amine” or “amino” includes compounds where anitrogen atom is covalently bonded to at least one carbon, hydrogen orheteroatom. The terms include, for example, but are not limited to,“alkyl amino,” “arylamino,” “diarylamino,” “alkylarylamino,”“alkylaminoaryl,” “arylaminoalkyl,” “alkaminoalkyl,” “amide,” “amido,”and “aminocarbonyl.” The term “alkyl amino” comprises groups andcompounds wherein the nitrogen is bound to at least one additional alkylgroup. The term “dialkyl amino” includes groups wherein the nitrogenatom is bound to at least two additional alkyl groups. The term“arylamino” and “diarylamino” include groups wherein the nitrogen isbound to at least one or two aryl groups, respectively. The term“alkylarylamino,” “alkylaminoaryl” or “arylaminoalkyl” refers to anamino group which is bound to at least one alkyl group and at least onearyl group. The term “alkaminoalkyl” refers to an alkyl, alkenyl, oralkynyl group bound to a nitrogen atom which is also bound to an alkylgroup.

EXAMPLES Abbreviations

The following abbreviations are used in the figures and text: THF(tetrahydrofuran); RT (room temperature); iPr₂NH (diisopropylamine);iPr₂NLi (lithium diisopropylamide); LDA (lithium diisopropylamide);H₂SO₄ (sulfuric acid); H₂O (water); IPA (isopropyl acetate); NaCl(sodium chloride); MsCl (methanesulfonyl chloride); NaH (sodiumhydride); n-BuLi (n-butyllithium); SF₄ (sulfur tetrafluoride); HCl(hydrochloric acid); HF (hydrofluoric acid).

Synthesis Procedures

To a solution of 1.5 equiv. of lithium diisopropylamide in THF at −15°C., freshly prepared from n-hexyllithium and diisopropylamine, was addeda solution of 1.0 equiv. of building block (1) in THF over 30 min. Theresulting deep brown-red solution was then stirred at −15° C. for 30min. Subsequently, a solution of 1.15 equiv. of Weinreb amide (2) in THFwas added over 30 min, and the reaction stirred at −15° C. for 1 hbefore being transferred onto a mixture of 1.5 molar aqueous sulfuricacid and toluene at 10° C. The biphasic mixture was vigorously stirredat room temperature for 25 min. Care was taken that the aqueous layerstayed at 2<pH<4, preferably pH 3. After phase separation, the organiclayer was washed with water, then concentrated at 50° C. under vacuum toca. 15-20% of its original volume to provide a solution of crude ketone(3) in toluene.

A solution of 1.0 equivalents of crude (3) in toluene is diluted withabsolute ethanol at room temperature, then 1.10 equivalents of thioureawas added. The yellow suspension is heated to 40° C., and approximately1.01 equivalents of solid N-bromosuccinimide was added in portions over30 min. After complete addition, the resulting red, clear solution wasstirred at 40° C. for 1 h. The reaction mixture was diluted withisopropyl acetate (IPA), and the fine, yellow-orange suspension wascooled to 0° C. over 1.5 h. Filtration over a sintered glass filter andsubsequent washing provided the wet reaction product (5), which wasfinally dried at 50° C. under vacuum.

To a yellow suspension of 1.0 equivalents of compound (5) in THF at roomtemperature was added 2.0 equivalents of pyridine. The reaction mixturewas heated to 40° C., then a solution of 1.0 equivalents of phenylchloroformate (7) in THF was added over 30 min. After stirring at 40° C.for 1 h, the reaction was cooled to RT, then saturated aqueous NaClsolution was added, and the biphasic mixture was stirred at RT for 10min before phase separation. The organic layer was heated to 60° C.,then a solution of 1.0 equivalents of L-prolinamide (IX) in water wasadded over 30 min. The reaction was stirred at 60° C. for 2 h, then thereaction mixture was cooled to 50° C., then toluene was added, followedby removal of THF via distillation under vacuum. The resultingsuspension was treated with water, and the reaction mixture was stirredat 50° C. for 30 min, before being cooled to 10° C. over 2 h. Afterstirring at 10° C. for another 30 min, the off-white suspension wasfiltered, and the filter cake washed with toluene, then dried at 50° C.under vacuum to give (10).

4-Methyl-2-(2,2,2-trifluoro-1-methyl-1-trimethylsilanyloxy-ethyl)pyridine(b)

To a fine, white suspension of sodium acetate (96.0 g, 117 mmol, 1.0equiv.) in 1 L DMSO was added 2-acetyl-4-methylpyridine (158 g, 117mmol, 1.0 equiv.). After dilution with another 0.5 L DMSO,trimethyl-trifluoromethylsilane (375 g, 264 mmol, 2.2 equiv.) was addedover 75 minutes. During the addition, the reaction vessel was placed ina cooling bath at 10° C. to keep the internal temperature between20-25°. The resulting dark suspension was stirred at room temperatureover night, then quenched carefully by addition of 1.5 L water over 20minutes. During the addition of water, the reaction vessel was placed ina cooling bath at −5° C. to keep the internal temperature between 10-25°C. After stirring at room temperature for 45 minutes, the mixture wasdiluted with 3 L ethyl acetate and stirred for another 15 minutes. Thephases were separated, and the water layer was extracted with 2 L ethylacetate. The combined organic phases were washed with 3 L saturatedaqueous NaHCO₃, dried over MgSO₄, filtered and concentrated in vacuo togive 346 g (106%, 88.6 area % by HPLC) of trifluoromethyl compound (b)as a brown, intensively smelling oil.

1,1,1-Trifluoro-2-(4-methylpyridin-2-yl)propan-2-ol (c)

To a solution of4-methyl-2-(2,2,2-trifluoro-1-methyl-1-trimethylsilanyloxy-ethyl)pyridine(b) (346 g, 125 mmol, 1.0 equiv.) in 1.5 L MeOH at room temperature wasadded solid K₂CO₃ (344 g, 249 mmol, 2.0 equiv.). The resulting beigesuspension was stirred at room temperature for 1 hour, then filteredover filter paper. The filtrate was concentrated in vacuo to give asolid, intensively smelling residue. The residue was dissolved in 1 Lethyl acetate and washed with water (2×1 L). After drying over MgSO₄ andfiltration, concentration in vacuo provided 252 g (98%) of alcohol (c)as an oil.

1,1,1-Trifluoro-2-(4-methylpyridin-2-yl)propan-2-yl methanesulfonate (d)

To a suspension of NaH (60% in mineral oil, 23.4 g, 585 mmol, 1.5equiv.) in 1 L THF at 0° C. was added a solution of1,1,1-trifluoro2-(4-methylpyridin-2-yl)propan-2-ol (c) (80 g, 390 mmol,1.0 equiv.) in 200 ml THF dropwise over 34 minutes. Gas evolutionoccurred, and the reaction mixture turned brownish. The reaction waswarmed to 40° C. and stirred at 40° C. for 45 minutes, when gasevolution had ceased. After cooling to room temperature, a solution ofmethanesulfonyl chloride (45.6 ml, 585 mmol, 1.5 equiv.) in 50 ml THFwas added dropwise over 30 minutes. The internal temperature rose to 36°C., and the reaction mixture turned into a light brown suspension. Thereaction mixture was warmed to 40° C. and stirred at this temperaturefor 15 minutes, then cooled to room temperature and further stirred overnight. The reaction was carefully quenched by addition of 750 ml waterwith cooling in an ice bath. The resulting brown biphasic mixture wasstirred at room temperature for 30 minutes, then the phases wereseparated. The aqueous layer was extracted with 750 ml ethyl acetate,and the combined organic phases were washed with saturated aqueousNaHCO₃. Drying over MgSO₄, filtration and concentration in vacuoprovided a beige solid. The residue was redissolved in 300 ml ethylacetate to give a turbid solution, then filtered over a plug of silicagel (120 g) and eluted with 600 ml ethyl acetate. Concentration in vacuoprovided a beige solid which was redissolved in 400 ml heptane and 150ml ethyl acetate at reflux. After hot filtration over a fritted funnel,the product crystallized at 0° C. The crystals were collected byfiltration, washed with cold heptane/ethyl acetate 8:3 (2×80 ml) anddried (50° C., 10 mbar) over night to give 94.0 g (85%) of mesylate (d)as white crystals.

4-methyl-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine (1)

To a suspension of 1,1,1-trifluoro-2-(4-methylpyridin-2-yl)propan-2-ylmethanesulfonate (d) (5.68 g, 20.1 mmol, 1.0 equiv.) in 60 mlcyclohexane at 10° C. was added AlMe₃ in hexane (2.0 M, 15.0 ml, 30mmol, 23.0 equiv.) dropwise over 15 minutes. The reaction was warmed atroom temperature and stirred at room temperature for 3 hours. Themixture was quenched by careful addition to 100 ml water at 0° C. andstirred at room temperature for 15 minutes. After filtration over a plugof cellflock and elution with ethyl acetate, the phases were separated.The aqueous layer was extracted with ethyl acetate, and the combinedorganic phases were washed with water and saturated aqueous NaCl. Afterdrying over Na₂SO₄, filtration and concentration in vacuo provided aslightly brownish oil, which was purified by chromatography on siligagel (hexane/TBME 9:1) to provide 1.15 g (28%) of the desired compound(1) as a colorless oil.

To a solution of n-butyllithium (2.04 equiv.) in 2-methyltetrahydrofuranat maximum −40° C. was added a solution of 2,4-dimethylpyridine (e)(2.02 equiv.) in 2-methyltetrahydrofuran over 60 min, keeping thetemperature below −30° C. The reaction mixture was stirred for 30 min atmaximum −30° C. A solution of diethyl carbonate (1.00 equiv.) in2-methyltetrahydrofuran was added over 60 min, keeping the temperaturebelow −30° C. The reaction was warmed to room temperature, and thenstirred at this temperature for 5 h. After cooling to 0° C., methyliodide (2.15 equiv.) was charged over 40 min, keeping the temperaturebelow 25° C. The reaction was further stirred at room temperature for 1h, then 1 M HCl was added, and the pH was adjusted to a value of pH 8-9.After stirring for 15 min, the phases were separated, and the organicphase was washed with water. Distillation at 35° C. under vacuum thenprovided crude dimethylated ester (f′). Ester (f′) was subsequentlyadded to a solution of sodium hydroxide (1.05 equiv.) in ethanol at 78°C. over 2 h. More ethanol was added, and the reaction was stirred at 78°C. for 10 h. The volume was reduced to approximately 50% by distillationunder normal pressure. After cooling to room temperature, tert-butylmethyl ether was added, and the reaction mixture was stirred at thistemperature for 30 min. Filtration was performed after cooling to 5-10°C., and the filter cake was washed with dichloromethane. The wet productwas dried at 60-70° C. under vacuum to give sodium carboxylate (g′).Compound (g′) was reacted with sulfur tetrafluoride and hydrofluoricacid to afford compound (1).

The invention claimed is:
 1. A process for making a compound of formula(X):

comprising the following steps: Step A: contacting a compound of formula(I) with the solvent tetrahydrofuran and a base lithium diisopropylamideat an internal temperature in the range of −15° C. to less than −5° C.,and contacting the resulting mixture with a compound of formula (II) atan internal temperature in the range of −15° C. to less than −5° C.,such that a compound of formula (III) is produced:

Step B: contacting a compound of formula (III) with thiourea, in areaction mixture comprising a solvent selected from toluene, an alcoholsolvent, or a combination thereof and an oxidizing agentN-bromosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin, such that acompound of formula (V) is produced:

Step C: contacting a compound of formula (V) with a compound of formula(VII), in a reaction mixture comprising the solvent tetrahydrofuran anda base amine, such that a compound of formula (VIII) is produced:

Step D: contacting a compound of formula (VIII) with the compound offormula (IX)

in a reaction mixture comprising a solvent selected fromtetrahydrofuran, water or a combination thereof, such that a compound offormula (X) is produced, wherein: R₁ is a branched or linear C₁-C₇alkyl, which may be optionally substituted one or more times withdeuterium, halogen, or C₃-C₅ cycloalkyl; R₂ is methyl; R₃ is C₆-C₁₄aryloxy, R₄ is halogen, and X is a halide.
 2. The process of claim 1,wherein the solvent of Step B comprises toluene and ethanol.
 3. Theprocess of claim 1 wherein the base of Step C is pyridine.
 4. Theprocess of claim 1, wherein the oxidizing agent of Step B isN-bromosuccinimide.
 5. The process of claim 1 wherein the solvent ofStep A comprises tetrahydrofuran, the base of Step A is lithiumdiisopropylamide, the solvent of Step B comprises toluene and ethanol,the oxidizing agent of Step B is N-bromosuccinimide, the solvent of StepC comprises tetrahydrofuran, the base of Step C is pyridine and thesolvent of Step D comprises tetrahydrofuran and water.
 6. The process ofclaim 1, wherein R₁ is

R₂ is methyl, R₃ is phenoxy, R₄ is chlorine, and X is bromine.
 7. Aprocess for making the compound of formula (10):

comprising the following steps: Step A: contacting the compound offormula (1) with the solvent tetrahydrofuran and a base lithiumdiisopropylamide at an internal temperature in the range of −15° C. toless than −5° C., and contacting the resulting mixture with the compoundof formula (2) at an internal temperature in the range of −15° C. toless than −5° C., such that the compound of formula (3) is produced:

Step B: contacting the compound of formula (3) with thiourea, in areaction mixture comprising a solvent selected from toluene, ethanol ora combination thereof and an oxidizing agent N-bromosuccinimide, suchthat the compound of formula (5) is produced:

Step C: contacting the compound of formula (5) with the compound offormula (7), in a reaction mixture comprising the solventtetrahydrofuran and a base amine, such that the compound of formula (8)is produced:

and Step D: contacting the compound of formula (8) with the compound offormula (IX)

in a reaction mixture comprising a solvent selected fromtetrahydrofuran, water or a combination thereof, such that the compoundof formula (10) is produced.
 8. The process of claim 1, wherein theresulting mixture of a compound of formula (I) and the solventtetrahydrofuran and base lithium diisopropylamide of Step A is contactedwith a compound of formula (II) at an internal temperature of −15° C. 9.The process of claim 1 wherein the solvent of Step D comprisestetrahydrofuran and water.
 10. The process of claim 7, wherein theresulting mixture of a compound of formula (1) and the solventtetrahydrofuran and base lithium diisopropylamide of Step A is contactedwith a compound of formula (2) at an internal temperature of −15° C. 11.The process of claim 1, wherein the solvent of step A is an alcoholsolvent, wherein the alcohol solvent is ethanol.